Renal cell carcinoma is the most common primary cancer arising from the kidney in adults, and is a frequent cause of cancer morbidity and mortality in the U.S., with over 12,000 deaths per year. Currently, there are no consistently effective chemotherapeutic or biologic treatment modalities for patients with advanced disease. Recent results of clinical trials in patients with advanced renal cancer (RC), and of pre-clinical studies using cell culture and human RC tissue specimens, suggest that natural and synthetic derivatives of vitamin A (retinol), a group of compounds called retinoids, play a role in the therapy of RC. We have preliminary data that intracellular levels of retinoic acid (RA) are significantly diminished in human RC cells and that retinol metabolism is aberrant in RC cells as compared to normal human kidney proximal tubule cells. Furthermore, our data indicate that combining retinoids with agents which augment retinoid actions, such as IFN (IFN) or histone deacetylase (HDAC) inhibitors, significantly increases the anti-tumor effect of RA. In this grant application, we propose to study the effects of modulating retinoid anti-tumor action by combining RA with other therapies. The specific aims are: 1) to perform a series of Phase I-II clinical trials designed to evaluate the safety and efficacy of combining liposomal all trans RA (ATRA) with modulators of RA such as interferon and HDAC inhibitors in patients with metastatic RC; 2) to collect peripheral blood samples and tumor tissues to allow laboratory analysis in order to monitor the presence and magnitude of specific therapies on retinoid metabolites and retinoid related genes; and 3) to analyze modulators of RA such as interferon and HDAC inhibitors at a molecular level in RC cell lines and xenograft models to delineate mechanisms of action, and to use this information to design strategies to test specific drugs in combination with RA in preparation for future clinical trials. These aims will allow us to perform clinical trials and laboratory studies aimed at gaining a better understanding of the involvement of retinoids in the development, progression and therapy of RC. Moreover, the experiments proposed in this application will help to clarify the potential use of retinoids as a therapeutic strategy to treat patients with RC, and may lead to the identification of new therapeutic agents which result in increased retinol actions for the treatment of various stages of renal cancer.